Our Ancestors’ Ghosts: Ancestral Exposure to Stress
Epigenetically Programs Preterm Birth Risk and Health Outcomes
Gerlinde A. S. Metz
Canadian Centre for Behavioural Neuroscience University of Lethbridge Alberta, Canada
Programming of the
Stress Response
Woods et al., AJOG, 2010
Stress generates a footprint that
travels
from one generation to the next…
Stress generates a footprint that
travels
from one generation to the next…
HYPOTHESIS: Ancestral Stress
Programs Maternal and Offspring
Health Trajectories
HYPOTHESIS: Ancestral Stress
Programs Maternal and Offspring
Health Trajectories
Does Stress Program Maternal
and Offspring Health?
Gestational Stress Disrupts
Maternal Behaviour
Zucchi et al., PLoS ONE, 2013
Can Stress During Pregnancy
Influence Preterm Birth Risk?
No Change in Gestational Length…
> 80 genes
involved in
neurological
diseases and
mental illness
Prenatal Stress Programs Gene
Expression Patterns
Zucchi et al., PLoS ONE, 2014
Zucchi et al., PLoS ONE, 2013
Gestational Stress Alters
Potentially Heritable Epigenetic
Markers
Can Stress Effects Propagate
to the Next Generations?
Can Stress Effects Propagate
to the Next Generations?
Can Stress Effects Propagate
to the Next Generations?
Can Stress Effects Propagate
to the Next Generations?
Unstressed Multigenerational
(S,SS, SSS, SSSS)
Transgenerational
(S, SN, SNN, SNNN)
Model of Transgenerational Maternal Stress
Ancestral Stress
Shortens Gestational Length
540 hrs. 529 hrs. 527 hrs.
Yao et al., BMC Medicine, 2014
Ancestral Stress Elevates
Blood Glucose Levels
Yao et al., BMC Medicine, 2014
Ancestral Stress Regulates the
miR-200 Family: Role in Pregnancy
Maintenance
Yao et al., BMC Medicine, 2014
miR-200 Family Regulates Genes
Involved in Pregnancy
Maintenance
Yao et al.,
BMC Medicine, 2014
Placental microRNA Signatures
as Proxies for Brain and Uterine
Health
F3 F3 F2 F2 F1
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Babenko, Kovalchuk et al., unpublished data
?
Ancestral Stress Impedes
Offspring Development
Yao et al., BMC Medicine, 2014
Ancestral Stress Impedes
Offspring Development
Yao et al., BMC Medicine, 2014
Erickson et al., PLOS One, 2014
Ancestral Stress
Alters Behaviour During
Vulnerable Periods in Life
** *
Remote Ancestral Stress Shifts
Patterns of Complex Diseases
Ambeskovic et al., unpublished data
Can Beneficial Experience
Offset Adverse
Programming?
Environmental Enrichment
Mitigates Adverse
Programming by Stress
McCreary, Erickson, et al., unpublished data
McCreary, Erickson, et al., unpublished data
Environmental Enrichment
Mitigates Adverse
Programming by Stress
Ancestral Stress May Better
Prepare Future Generations
?????
Benefits
• Resilience
• Metabolic
Preparation
Ancestral Stress
Also Bears Health Risks
?????
Benefits
• Resilience
• Metabolic
Preparation
Risks
• Cardiovascular
• Metabolic
• Aging
Benefits
• Resilience
• Metabolic
Preparation
Risks
• Cardiovascular
• Metabolic
• Aging
Transgenerational Programming
of Maternal and Offspring Health
Benefits
• Resilience
• Metabolic
Preparation
Risks
• Cardiovascular
• Metabolic
• Aging
Transgenerational Programming
of Maternal and Offspring Health
Building the Foundation for Healthy Futures
• Ancestral stress is a significsnt influence on lifetime health trajectories.
• Transgenerational inheritance involves epigenetic mechanisms.
• Transgenerational studies may identify new predictive biomarkers of disease.
Acknowledgements University of Lethbridge
Canadian Centre for Behavioural Neuroscience
Dr. Bryan Kolb
Tony Montina
Dept. of Biol. Sciences
Dr. Igor Kovalchuk
Dr. Olga Kovalchuk
• Dr. David M. Olson (University of Alberta)
• Dr. Suzanne King (McGill University)
Alberta Innovates
Health Solutions
Alberta Innovates
Health Solutions
Alberta Innovates
Health Solutions
Alberta Innovates
- Health Solutions
Questions?
Does Stress
Induce
Genuine
Trans-
generational
Effects?
Programming of the
Stress Response
Great Great Grandmother
Great Grandmother
Grandmother
Mother
YOU!
Proposed Mechanisms of
Action of miR-200
Proposed mechanisms of action of miR200, ZEB1,2
and STAT5b - Carole Mendelson Lab
Williams et al., PNAS, 2012; 109:7529-34
Transgenerational Epigenetic
(microRNA) Programming of
Cortical Development
** **
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Babenko, Kovalchuk, et al., unpublished data
Down-Stream Metabolic
Signatures of Stress
Example: F3-SNN Kiss, Montina, et al., unpublished
Ambeskovic et al., 2013
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0
20
40
60
80
100
120
140
160
180
200
Cadmium (Cd) Potassium (K) Sodium (Na) Zinc (Zn)
%C
on
ten
tC
han
ge
Myocardial Infarct
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Metabolic Signatures of
Age-related Diseases in Hair
HYPOTHESIS: Ancestral Stress
Programs Maternal and Offspring
Health Trajectories
